Challenges of treating hypertension:

1
The cardiovascular dysmetabolic syndrome
Hypertension
Obesity
Atherosclerosis
Hypfeinsulinemia
Diabetes
Insulin resistance
Hypertriglyceridemia
Small, dense LDL
Endothelialdysfunction
Low HDL
Hypercoagulability
Am. J. Med., 1998 105(1A) 1S-3S
2
Insulin Resistance in Asian Indians and Europeans
12
8
Glucose uptake (mg/kg/min)
4
0
European Indian
Horm. Metab. Res. 1987 1984-85
3
Metabolic abnormalitiesassociated with insulin
resistance

• Small, dense low-density lipoprotein
• Central body fat
• Free fatty acids
• Triglyceride synthesis
• Triglyceride elimination
• High-density lipoprotein
• Insulin

• Proinsulin
• Plasminogen-activator inhibitor-1
• Sympathomimetic activity
• Sodium retention
• Blood pressure
• Vasodilatory

Sethi K K. CAD in Indians, CSI, 1998
4
Glucose Tolerance in Asian Indians and Europeans
Diabetologia, 1986 29235-237
5
The prevalence of coexistence of dyslipidemia
and hypertension in the patients surveyed at
Apollo Hospitals (n501)
Indian Heart Journal 1996 48(4) 371-374
6
Effect of various antihypertensives on coexisting
disorders

• Total LDL- HDL- Serum Glucose Insulin cholestero
  l cholesterol cholesterol triglycerides tolerance
  sensitivity
• Diuretic
• b-blockers - - -
• ACEinhibitors - - - -
• Allantagonists - - - -
• CCBs - - - - - -
• a-blockers

7
Change in Lipid Levels with Doxazosin Treatment
HALT Study
Total-C
LDL-C
Triglycerides
HDL-C
Change in Lipid Levels (mg/dl)
Am Heart J 1996131 966-973
8
Changes in Lipid Parameters after 24 weeks
Triglyc
HDL Total Chol.
HDL Chol.
Total Chol.
Average (S.E.)
Am J Card 198759103G
9
Doxazosin v/s Atenolol in Hypertension

• Comparable reduction in blood pressure
• Effect on serum lipids
• Drug Baseline Final Change
• Cholesterol Doxazosin 211.8 105.6 -2.91.1
• Atenolol 207.0 201.8 -2.31.4
• Triglycerides Doxazosin 119.9 106.7 -11.13.7
• Atenolol 120.2 132.7 10.43.3
• HDL Doxazosin 49.5 50.6 2.11.6
• Atenolol 45.0 42.2 - 6.21.7
• Am J Card 1987 5990G

10
How does doxazosin reduce lipids

• Upregulation of LDL receptors
• Decreased cholesterol synthesis
• Decreased absorption of cholesterol from GIT
• Decrease in lipoprotein lipase activity
• Inhibition of VLDL synthesis

11
Doxazosin in Hypertensives with NIDDM (n35, 24
weeks)

• Parameter Baseline End of P Value Treatment
• Systolic BP 17215 14919 lt 0.001
• Diastolic BP 9011 8210 lt 0.001
• HbAIC () 7.431.19 7.051.17 lt 0.05
• Cholesterol 20939 19838(md/dl) (25233) (22033
  ) lt 0.05
• Triglyceride 11354 9849 lt 0.05(mg/dl)
• J Int Med Res 1996 24 138-46

12
Effect of Doxazosin on insulin sensitivity
inhypertensives with NIDDM

• Captopril Nifedipine Doxazosin
• Plasma glucose No change No change Decrease
• Free fatty acid No change No change Decrease
• concentration
• Insulin mediated No change No change Increase
• Glucose uptake
• Glucose oxidation No change No change Increase
• and disposal
• Plasma lipids No change No change Improved
• Diabetes 1995 44 665-71

13
Doxazosin and CHD risk reduction

• Beneficial effect on lipids
• Beneficial effect on insulin resistance
• Improved fibrinolytic activity
• Reduces left ventricular hypertrophy
• All these should effectively reduce
• the risk of CHD

14
Effect of various drugs on CHD risk

• Drug Effect on CHD risk
• Doxazosin 15-45
• Enalapril 18
• Captopril 19
• Atenolol 14 25
• Drugs 1995